This invention relates to remedies for colonic motor dysfunction, and more specifically to colonic motor dysfunction remedies comprising aminothiazole derivatives as active ingredients. This invention is also concerned with a treatment method for colonic motor dysfunction.
From the anatomical viewpoint, the digestive tract is divided roughly into an upper digestive tract and a lower digestive tract. The upper digestive tract includes the esoplagus, the stomach and the duodenum, while the lower digestive tract includes the small intestine, the large intestine and the rectal. To diseases and symptoms which occur in the respective regions, treatments are applied correspondingly.
Illustrative of diseases of the upper digestive tract are diseases in the esophageal region, such as esophageal carcinoma, esophagostenosis and reflux esophagitis; diseases in the gastric region, such as gastric ulcer, gastritis and gastric cancer; diseases in the duodenal region, such as duodenal ulcer and duodenal cancer; and as diseases occurring commonly in the gastric region and duodenal region, NUD (Non-Ulcer Dyspepsia) and gastroduodenal motor dysfunction. Examples of symptoms of such diseases of the upper digestive tract with which gastroduodenal motor dysfunction is associated include epigastric malaise, nausea, vomitting, brash, anorexia, bellyache, and dilatation of the stomach.
Illustrative of diseases of the lower digestive tract are colon cancer, colon polyp, ulcerative collitis, Crohn""s disease, irritable bowel syndromes, constipation, intestinal atony, and drug-induced motor dysfunction. Of these, irritable bowel syndromes, constipation, intestinal atony and drug-induced motor dysfunction are diseases attributable to motor dysfunction of the large intestine, and are known to develop a cathartic disorder, such as constipation or diarrhea, and/or bellyache. Drug-induced motor dysfunction, on the other hand, is known to occur as a result of use of a calcium antagonist, a psychotropic or an antidepressant [Cardiology, 89(suppl. 1), 10-15, 1998; J. Clin. Psychopharmacol., 19, 401-406, 1999; Pharmacotherapy, 11, 179-195, 1991].
As improvers for irritable bowel syndromes, trimebutine maleate, allosetron hydrochloride and tegaseroid maleate are known. Of these, trimebutine maleate has been found to give side effects on the central nerve system (sleep, dizziness and the like) via opioid receptors. With respect to allosetron hydrochloride and tegaseroid maleate which are effective for diarrheal IBS and constipated IBS, respectively, there is an outstanding concern about side effect of constipation as an excess effect because drug efficacy is developed via serotonin receptors.
As gastroprokinetic agents for the upper digestive tract, cisapride, metoclopramide, itopride hydrochloride, mosapride citrate and the like are known (Gastroenterology, 118, S32-S47, 2000). However, these improvers have been reported to be ineffective for constipation associated with irritable bowel syndromes which are diseases caused by colonic motor dysfunction (J. Clin. Pharmacol., 19, 617-625, 1979; Scand. J. Gastroenterol., 33, 128-131, 1998;Aliment. Pharmacol. Ther., 11, 387-394, 1997).
PCT International Publications WO96/36619 and WO98/17654 disclose that aminothiazole derivatives enhance gastric motor activity and improve epigastric malaise, nausea, vomitting, brash, anorexia, bellyache, and dilatation of the stomach. These publications, however, make no mention about improving effects on diseases of the lower digestive tract caused by colonic motor dysfunction.
There is, accordingly, an outstanding desire for the development of improvers for colonic motor dysfunction, which are free of such side effects as those observed on the conventional irritable bowel syndrome improvers and caused via opioid receptors or serotonin receptors.
The present invention provides a colonic motor dysfunction remedy comprising, as an active ingredient, an aminothiazole derivative represented by the following formula (I) or a salt or hydrate thereof: 
wherein R1, R2 and R3 may be the same or different and each independently represent a hydrogen atom or a hydroxyl, lower alkyl, lower alkoxy, amino, nitro or cyano group, R4 and R5 may be the same or different and each independently represent a hydrogen atom or a lower alkyl group, and n stands for an integer of from 2 to 4.
The present invention also provides use of an amino-thiazole derivative represented by the formula (I) or a salt or hydrate thereof for the production of a colonic motor dysfunction remedy.
The present invention also provides a treatment method for colonic motor dysfunction, which comprises administering an effective amount of an aminothiazole derivative represented by the formula (I) or a salt or hydrate thereof.
In the aminothiazole derivative (I) useful in the practice of the present invention, the term xe2x80x9clower alkylxe2x80x9d means a linear, branched or cyclic, saturated hydrocarbon group which preferably has 1 to 6 carbon atoms. On the other hand, the term xe2x80x9clower alkoxyxe2x80x9d means a group formed of a linear, branched or cyclic, saturated hydrocarbon, which preferably has 1 to 6 carbon atoms, and an oxygen atom bonded to the hydrocarbon.
Accordingly, illustrative of the xe2x80x9clower alkyl groupxe2x80x9d as R1, R2, R3, R4 and R5 are linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methyl-pentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, and cyclohexyl. Among these, more preferred lower alkyl groups are linear or branched alkyl groups having 1 to 4 carbon atoms. Particularly preferred as R4 and R5 is isopropyl. Particularly preferred as R1, R2 and R3 are H, hydroxy, methoxy, amino, nitro and cyano.
Illustrative of the xe2x80x9clower alkoxy groupxe2x80x9d as R1, R2 and R3 are linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, isopentoxy, tert-pentoxy, 1,2-dimethylpropoxy, neopentoxy, 1-ethylpropoxy, cyclopentoxy, hexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, isohexyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethyl-propoxy, and cyclohexyloxy. Among these, more preferred lower alkoxy groups are linear or branched alkoxy groups having 1 to 4 carbon atoms. Particularly preferred is methoxy.
As n, 2 is particularly preferred.
Preferred examples of the aminothiazole derivative (I) useful in the practice of the present invention can include compounds in which R1, R2 and R3 are the same or different and each independently represent a hydroxyl group or a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, specifically a methoxy group or one of R1, R2 and R3 is an amino, nitro or cyano group and the remaining two substituents are hydrogen atoms; R4 and R5 are the same and each represent an alkyl group having 1 to 6 carbon atoms, specifically an isopropyl group; and n is 2. Illustrative of particularly preferred compounds are
N-(Nxe2x80x2,Nxe2x80x2-diisopropylaminoethyl)-[2-(2-hydroxy-4,5-dimethoxy benzoylamino)-1,3-thiazol-4-yl] carboxamide,
N-(Nxe2x80x2,Nxe2x80x2-diisopropylaminoethyl)-[2-(3-cyano-benzoylamino)-1,3-thiazol-4-yl]carboxamide, and
N-(Nxe2x80x2,Nxe2x80x2-diisopropylaminoethyl)-[2-(3-aminobenzoylamino)-1,3-thiazol-4-yl]carboxamide.
Examples of the salt of the aminothiazole derivative (I), which is also useful in the practice of the present invention, can include inorganic acid addition salts, such as the hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide; and organic acid addition salts, such as the acetate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate and ethansulfonate. A preferred example of the salt is the hydrochloride.
The aminothiazole derivative (I) useful in the practice of the present invention includes various solvates such as hydrate.
The aminothiazole derivative (I) useful in the practice of the present invention can be prepared by the process disclosed in PCT International Publication WO96/36619 or WO98/17654.
In the present invention, the aminothiazole derivative (I) can be formulated together with a pharmaceutically acceptable carrier into a composition for oral administration or parenteral administration. As compositions for oral administration, the aminothiazole derivative (I) useful in the practice of the present invention can be formulated into tablets, powder, granules or capsules by using suitable additives, for example, an excipient such as lactose, mannitol, corn starch or crystalline cellulose; a binder such as a cellulose derivative, gum arabic or gelatin; a disintegrator such as carboxy-methylcellulose calcium; a lubricant such as talc or magnesium stearate; and the like. Further, these solid preparations can be formed into enteric preparations by using a coating base such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate or a methacrylate copolymer. As compositions for parenteral administration, the aminothiazole derivative (I) useful in the practice of the present invention can be formulated into liquid preparations for injection, for example, by making combined use of water, ethanol, glycerin, a commonly employed surfactant and the like, or into suppositories by using a suppository base.
In the present invention, the dosage of the aminothiazole derivative (I) may range generally from 0.1 to 2,000 mg/day, preferably from 1 to 300 mg/day, notably from to mg/day in the case of oral administration although it varies depending on the age, weight, symptom, effects of treatment, administration method, and administration period. It is preferred to administer this dosage in a range of from 1 to 3 times a day.
As the aminothiazole derivative (I) useful in the practice of the present invention have excellent colomotor enhancing effect and high safety as will be described subsequently herein, it is useful as a remedy for colonic motor dysfunction of mammals including human being. Illustrative of colonic motor dysfunction are irritable bowel syndrome, constipation, intestinal atony, and drug-induced motor dysfunction. It does not act on serotonin receptors or dopamine receptors [Gastroenterology, 116(4) part 2, A1094, 1999] and different from conventional drugs, do not have side effects such as side effects on the central nerve system, e.g., extrapyramidal disorders and dizziness, and constipation as an excess effect.